Chronic hypoxia attenuates nitric oxide-dependent hemodynamic responses to acute hypoxia

Alterations in the nitric oxide (NO) pathway have been implicated in the pathogenesis of chronic hypoxia-induced pulmonary hypertension. Chronic hypoxia can either suppress the NO pathway, causing pulmonary hypertension, or increase NO release in order to counteract elevated pulmonary arterial pressure. We determined the effect of NO synthase inhibitor on hemodynamic responses to acute hypoxia (10% O(2)) in anesthetized rats following chronic exposure to hypobaric hypoxia (0.5 atm, air). In rats raised under normoxic conditions, acute hypoxia caused profound systemic hypotension and slight pulmonary hypertension without altering cardiac output. The total systemic vascular resistance (SVR) decreased by 41 +/- 5%, whereas the pulmonary vascular resistance (PVR) increased by 25 +/- 6% during acute hypoxia. Pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) attenuated systemic vasodilatation and enhanced pulmonary vasoconstriction. In rats with prior exposure to chronic hypobaric hypoxia, the baseline values of mean pulmonary and systemic arterial pressure were significantly higher than those in the normoxic group. Chronic hypoxia caused right ventricular hypertrophy, as evidenced by a greater weight ratio of the right ventricle to the left ventricle and the interventricular septum compared to the normoxic group (46 +/- 4 vs. 28 +/- 3%). In rats which were previously exposed to chronic hypoxia (half room air for 15 days), acute hypoxia reduced SVR by 14 +/- 6% and increased PVR by 17 +/- 4%. Pretreatment with L-NAME further inhibited the systemic vasodilatation effect of acute hypoxia, but did not enhance pulmonary vasoconstriction. Our results suggest that the release of NO counteracts pulmonary vasoconstriction but lowers systemic vasodilatation on exposure to acute hypoxia, and these responses are attenuated following adaptation to chronic hypoxia.     

Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia

We sought to determine whether chronic exposure tointermittent hypoxia (CIH) increases sympathetic responsiveness tosubsequent chemoreflex stimulation. Sprague-Dawley rats were exposed to30 days of CIH: exposure chamber%O₂ [fractionalconcentration of chamber O₂(Fc_O2)]nadir 6.5-7% with return to 21% each minute for 8 h/day duringthe diurnal sleep period (Exp group). Sham controls (SC group) weresimilarly handled but kept at 21%Fc_O2 andcompared with unhandled controls (UC group). Rats were then anesthetized with urethan, and preganglionic cervical sympathetic activity (CSA), diaphragm electromyogram, arterial pressure, and electrocardiogram were recorded while the rats were spontaneously breathing 100% O₂, room air, 10%O₂, 12%CO₂, and 10%O₂-12%CO₂. CSA and heart rate were alsorecorded during phenylephrine infusion to assess baroreceptor function.Mean arterial pressure was significantly greater in Exp than in SC andUC rats during all conditions (P < 0.05). A vasopressor response to 10%O₂-12%CO₂ was observed only in Exp rats.CSA was greater in Exp than in SC and UC rats during 10%O₂, 12%CO₂, and 10%O₂-12%CO₂ but not during room-air exposure. A significant increase in CSA compared with room air wasnoted during 10% O₂, 12%CO₂, and 10%O₂-12%CO₂ in Exp but not in SC or UCrats. No differences in baroreceptor function were observed amonggroups. We conclude that CIH leads to increased sympatheticresponsiveness to chemoreflex stimulation.

     

Insects in hypoxia

Insects exhibit a remarkable array of adaptations that allow them to handle more or less severe hypoxia associated with numerous aquatic and terrestrial habitats. We consider these habitats and then discuss physiological, behavioral and morphological mechanisms that facilitate insect life under oxygen deprivation. Actually or potentially hypoxic habitats include aquatic systems, flood-prone soils and burrows, intertidal zones, ice encasement and high altitudes. Some microhabitats, including dung, carrion, mammalian alimentary canals, grain and wood, also are subject to hypoxia. Adaptations to hypoxia include the ability to switch from aerobic to anaerobic metabolic pathways (with attendant generation of end products), the ability to drastically attenuate basal metabolic rates, altered behaviors and enlarged tracheal system volumes. Research into the biology of hypoxia seems to be progressing from early observations of the abilities of some insects to withstand exposure to hypoxia or anoxia through studies of organismal mechanisms operating in hypoxia to detailed investigations of cellular and intracellular signaling processes. Our hope is this essay will help crystallize the emergent picture of this area for those interested in contributing to future research.     

Dihydroceramide-based response to hypoxia

To understand the mechanisms of ceramide-based responses to hypoxia, we performed a mass spectrometry-based survey of ceramide species elicited by a wide range of hypoxic conditions (0.2-5% oxygen). We describe a rapid, time-dependent, marked up-regulation of dihydroceramides (DHCs) in mammalian cells and in the lungs of hypoxic rats. The increase affected all DHC species and was proportional with the depth and duration of hypoxia, ranging from 2- (1 h) to 10-fold (24 h), with complete return to normal after 1 h of reoxygenation at the expense of increased ceramides. We demonstrate that a DHC-based response to hypoxia occurs in a hypoxia-inducible factor-independent fashion and is catalyzed by the DHC desaturase (DEGS) in the de novo ceramide pathway. Both the impact of hypoxia on DHC molecular species and its inhibitory effect on cell proliferation were reproduced by knockdown of DEGS1 or DEGS2 by siRNA during normoxia. Conversely, overexpression of DEGS1 or DEGS2 attenuated the DHC accumulation and increased cell proliferation during hypoxia. Based on the amplitude and kinetics of DHC accumulation, the enzymatic desaturation of DHCs fulfills the criteria of an oxygen sensor across physiological hypoxic conditions, regulating the balance between biologically active components of ceramide metabolism.     

Ecosystem thresholds with hypoxia

Hypoxia is one of the common effects of eutrophication in coastal marine ecosystems and is becoming an increasingly prevalent problem worldwide. The causes of hypoxia are associated with excess nutrient inputs from both point and non-point sources, although the response of coastal marine ecosystems is strongly modulated by physical processes such as stratification and mixing. Changes in climate, particularly temperature, may also affect the susceptibility of coastal marine ecosystems to hypoxia. Hypoxia is a particularly severe disturbance because it causes death of biota and catastrophic changes in the ecosystem. Bottom water oxygen deficiency not only influences the habitat of living resources but also the biogeochemical processes that control nutrient concentrations in the water column. Increased phosphorus fluxes from sediments into overlying waters occur with hypoxia. In addition, reductions in the ability of ecosystems to remove nitrogen through denitrification and anaerobic ammonium oxidation may be related to hypoxia and could lead to acceleration in the rate of eutrophication. Three large coastal marine ecosystems (Chesapeake Bay, Northern Gulf of Mexico, and Danish Straits) all demonstrate thresholds whereby repeated hypoxic events have led to an increase in susceptibility of further hypoxia and accelerated eutrophication. Once hypoxia occurs, reoccurrence is likely and may be difficult to reverse. Therefore, elucidating ecosystem thresholds of hypoxia and linking them to nutrient inputs are necessary for the management of coastal marine ecosystems. Finally, projected increases in warming show an increase in the susceptibility of coastal marine ecosystems to hypoxia such that hypoxia will expand. Guest editors: J. H. Andersen & D. J. Conley Eutrophication in Coastal Ecosystems: Selected papers from the Second International Symposium on Research and Management of Eutrophication in Coastal Ecosystems, 20–23 June 2006, Nyborg, Denmark     

Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans.

Short-term intermittent hypoxia leads to sustained sympathetic activation and a small increase in blood pressure in healthy humans. Because obstructive sleep apnea, a condition associated with intermittent hypoxia, is accompanied by elevated sympathetic activity and enhanced sympathetic chemoreflex responses to acute hypoxia, we sought to determine whether intermittent hypoxia also enhances chemoreflex activity in healthy humans. To this end, we measured the responses of muscle sympathetic nerve activity (MSNA, peroneal microneurography) to arterial chemoreflex stimulation and deactivation before and following exposure to a paradigm of repetitive hypoxic apnea (20 s/min for 30 min; O(2) saturation nadir 81.4 +/- 0.9%). Compared with baseline, repetitive hypoxic apnea increased MSNA from 113 +/- 11 to 159 +/- 21 units/min (P = 0.001) and mean blood pressure from 92.1 +/- 2.9 to 95.5 +/- 2.9 mmHg (P = 0.01; n = 19). Furthermore, compared with before, following intermittent hypoxia the MSNA (units/min) responses to acute hypoxia [fraction of inspired O(2) (Fi(O(2))) 0.1, for 5 min] were enhanced (pre- vs. post-intermittent hypoxia: +16 +/- 4 vs. +49 +/- 10%; P = 0.02; n = 11), whereas the responses to hyperoxia (Fi(O(2)) 0.5, for 5 min) were not changed significantly (P = NS; n = 8). Thus 30 min of intermittent hypoxia is capable of increasing sympathetic activity and sensitizing the sympathetic reflex responses to hypoxia in normal humans. Enhanced sympathetic chemoreflex activity induced by intermittent hypoxia may contribute to altered neurocirculatory control and adverse cardiovascular consequences in sleep apnea.     

Differentiation arrest by hypoxia

The stem cell niche is a unique tissue microenvironment that regulates the self-renewal and differentiation of stem cells. Although several stromal cells and molecular pathways have been identified, the microenvironment of the stem cell niche remains largely unclear. Recent evidence suggests that stem cells are localized in areas with low oxygen. We have hypothesized that hypoxia maintains the undifferentiated phenotype of stem/precursor cells. In this report, we demonstrate that hypoxia reversibly arrests preadipocytes in an undifferentiated state. Consistent with this observation, hypoxia maintains the expression of pref-1, a key stem/precursor cell gene that negatively regulates adipogenic differentiation. We further demonstrate that the hypoxia-inducible factor-1 (HIF-1) constitutes an important mechanism for the inhibition of adipogenic differentiation by hypoxia. Our findings suggest that hypoxia in the stem cell niche is critical for the maintenance of the undifferentiated stem or precursor cell phenotype.     

Transferrin glycosylation in hypoxia

The aim of this study was to examine the effect of reduced O2 tension on the glycosylation of transferrin. Rats were placed in a hypobaric chamber (380 mmHg) that corresponded to an altitude of 5486 m above sea level for 21 days. The animals responded with marked increases in hematocrit (from 44 to 76%) and cardiac weight, and with reductions in the concentration of plasma transferrin averaging 15%. Analyses of their plasma transferrin by serial anion-exchange and lectin affinity chromatography revealed no changes in the extent of glycan branching. However, there was a moderate rise in the proportion of fucosylated transferrin molecules (fucosylation index) and a slight decrease in the transferrin fraction bearing a tetrasialylated biantennary glycan. The fucosylation index correlated positively with plasma transferrin concentrations in the test animals, but not in the controls. In contradistinction to the situation with transferrin, hypoxic rats exhibited a reduced fucosylation index of immunoglobulin G.